The fungal opportunistic pathogen, Pneumocystis (Pc) jirovecii is the causative agent of Pneumocystis pneumonia (PCP), which is of increasing concern in persons receiving immunosuppressive therapies, including organ transplant recipients, cancer patients, individuals with inflammatory disease and in persons experiencing natural immunosuppression due to aging, congenital or acquired immunosuppressive states. In addition, in clinical studies and in non-human primate models, we have shown that persistent Pc colonization is also associated with the development of chronic obstructive pulmonary disease (COPD). Long-term goals of our work are to develop vaccine strategies for the prevention of Pc infection and related pulmonary sequelae in immunocompromised populations and to develop innovative strategies for improved therapies for acute PCP in immunocompromised individuals. To achieve these goals, we have developed pre-clinical, non-human primate models of PCP in drug-induced immunosuppressed animals. We have previously identified a recombinant protein sub-unit vaccine, KEX1, that induces robust anti-Pc immunity in non-human primates that is durable and protective against PCP following profound immunosuppression induced by simian immunodeficiency virus infection (SIV) and reported that antibodies to KEX1 are associated with prevention of PCP in human immunocompromised individuals. The objectives to be addressed in the proposed studies are 1) to determine the protective efficacy of the KEX1 vaccine in pre-clinical models of therapeutic immunosuppressive regimens, (e.g., as in organ transplantation) and 2), to harness our extensive data regarding the protective nature of the humoral responses to KEX1 for the development and testing of monoclonal antibodies (mAb) for use in treating acute PCP. We hypothesize that the KEX1 vaccine will induce durable and protective immunity against PCP in immunocompromised individuals. We further hypothesize that treatment of acute PCP with KEX1 mAbs will contribute to resolution of pneumonia and mitigate pulmonary damage associated with the infection. Aim 1 will test the hypothesis that immunization with KEX1 vaccine will elicit protective memory responses and will provide protection from PCP in immunocompromised NHPs. We will evaluate the durability and protective efficacy of the immune response during immunosuppressive therapy. NHPs will be challenged via natural exposure to Pneumocystis and evaluated for clinical disease, immunity, pulmonary function and pathology. Aim 2 will test the hypothesis that KEX1-specific mAbs will effectively treat established PCP in an immunosuppression NHP model. Our innovative technology in mAb generation, combined with a unique and clinically relevant model of PCP in immunosuppressed monkeys, will allow us to define the utility of KEX1 mAbs in treating PCP and advance a novel therapeutic avenue for this disease.